EP1814901B1 - Von fibrin abgeleitete citrullinpeptide, die durch für rheumatoide arthritis spezifische autoantikörper erkannt werden, und deren verwendung - Google Patents

Von fibrin abgeleitete citrullinpeptide, die durch für rheumatoide arthritis spezifische autoantikörper erkannt werden, und deren verwendung Download PDF

Info

Publication number
EP1814901B1
EP1814901B1 EP05815291A EP05815291A EP1814901B1 EP 1814901 B1 EP1814901 B1 EP 1814901B1 EP 05815291 A EP05815291 A EP 05815291A EP 05815291 A EP05815291 A EP 05815291A EP 1814901 B1 EP1814901 B1 EP 1814901B1
Authority
EP
European Patent Office
Prior art keywords
peptide
citrullyl
residue
sequence
residues
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP05815291A
Other languages
English (en)
French (fr)
Other versions
EP1814901A1 (de
Inventor
Guy Résidence du Lac-Appartement 46 SERRE
Mireille Sebbag
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biomerieux SA
Original Assignee
Biomerieux SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from FR0411782A external-priority patent/FR2877345B1/fr
Priority claimed from FR0413711A external-priority patent/FR2879604B1/fr
Application filed by Biomerieux SA filed Critical Biomerieux SA
Publication of EP1814901A1 publication Critical patent/EP1814901A1/de
Application granted granted Critical
Publication of EP1814901B1 publication Critical patent/EP1814901B1/de
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/745—Blood coagulation or fibrinolysis factors
    • C07K14/75—Fibrinogen

Definitions

  • the present invention relates to novel citrullinated peptides recognized by autoantibodies specific to rheumatoid arthritis.
  • RA Rheumatoid arthritis
  • RA Rheumatoid arthritis
  • serum of patients with autoantibodies some of which are specific, and can be a marker of this disease, allowing its diagnosis even at early stages.
  • Research has therefore been carried out in order to identify antigens recognized by these antibodies, in order to obtain purified preparations which can be used in standard immunodiagnostic techniques.
  • RA-specific autoantibodies recognize different isoelectric variants of (pro) filaggrin (for review, see for example GREENHOUSE and VINCENT, In: Autoantibodies, PETER and SHOENFELD Eds, Elsevier Science Publishers, 271-276, 1996 ). These autoantibodies have for this reason been called “anti-filaggrin autoantibodies (AAF)".
  • Requirement EP 0 511 116 describes the purification and characterization of antigens of the family of filaggrins recognized by these antibodies, and their use for the diagnosis of rheumatoid arthritis.
  • the epafopes of filaggrin recognized by AAF were identified as regions of the filaggrin molecule carrying citrullyl residues, resulting from the transformation of arginyl residues by a peptidylarginine deiminase ( Girbal-Neuhauser E et al., J Immunol, 162, 585-94, 1999 ; Schellekens GA et al., J Clin Invest, 101, 273-81, 1998 ).
  • the analysis of various synthetic peptides derived from the sequence of human filaggrin showed that the elimination (citrullination) was necessary for the constitution of the epitopes recognized by the AAF, which are today also called citrullinated protein autoantibodies (AAPC). This name will be used in the following description.
  • citrullyl residue environment also plays an important role (Girbal-Neuhauser E, 1999, cited above, Schellekens GA, 1998, cited above; Union A et al., Arthritis Rheum, 46, 1185-95, 2002 ); some amino acids "permissive" to antibody binding and whose nature probably modulates the binding affinity of the antibody have been identified.
  • the -gly-, -ser-, -his-, -thr- and -gln- residues are most often found in the immediate environment of the citrullyl residues of the citrullinated "filaggrin" peptides which, to date, have been identified as carriers of epitopes recognized by the ACPAs ( Sebbag M et al., Rev Rhum, 68, 106, 2001 ).
  • citrullinated peptides specifically recognized by AAPC were obtained from filaggrin.
  • AAPCs Numerous citrullinated peptides specifically recognized by AAPC, and used for the diagnosis of RA, were obtained from filaggrin.
  • the reactivity of these different citrullinated peptides with respect to AAPCs was heterogeneous, with different peptides being recognized by sera from different subjects. This implies that to obtain a diagnostic reagent capable of identifying the presence of AAPC in a large population, it is necessary to associate several different peptides.
  • ACPAs are secreted by the plasma cells of synovial tissue ( Masson-Bessière C et al., Clin Exp Immunol, 119, 544-52, 2000 ) and are specifically directed against citrullinated forms of ⁇ and ⁇ chains of fibrin present in this tissue ( Masson-Bessière C et al., J Immunol, 166, 4177-84, 2001 ).
  • WO 01/02437 and Sebbag et al. disclose the use of citrullinated derivatives of fibrin for the diagnosis of rheumatoid arthritis.
  • Nijenhuis et al. (Clinica Chimica Acta vol.350, 2004, p.17-34 ) discuss the advantages of citrullinated peptides over citrullinated proteins for the diagnosis of rheumatoid arthritis.
  • the inventors have undertaken, in order to better characterize the epitopes recognized by the ACPAs, to identify those presented by the ⁇ and ⁇ chains of the fibrin. For this purpose, they evaluated the reactivity of AAPC-containing sera against synthetic citrullinated peptides derived from the ⁇ chain sequence and the fibrin ⁇ chain sequence. Given the known heterogeneity of the reaction profiles of citrullinated peptides derived from filaggrin with AAPC, the inventors have used mixtures of sera chosen to contain AAPC representing the different reactivity profiles observed in the case of these peptides from filaggrin, in order to detect all the fibrin peptides that can be recognized by AAPC.
  • the peptides tested were obtained from the sequence of the ⁇ chain and the ⁇ chain sequence of fibrin. A total of 72 peptides, including 41 derivatives of the ⁇ chain of fibrin and 31 derivatives of its ⁇ chain were chosen. Among the 72 citrullinated peptides analyzed, the inventors have identified 13 peptides derived from the sequence of the ⁇ chain and 5 peptides derived from that of the ⁇ chain of fibrin as being significantly reactive with one or both of the mixtures of serums tested, and therefore as carrying epitopes recognized by some of the ACPA present in this mixture (s).
  • the inventors then individually analyzed each of the 18 reactive peptides identified with each of the sera constituting the mixtures tested. This analysis confirmed, for the majority of the peptides tested, the wide interindividual variability of AAPC specificity previously observed in the case of citrulline peptides derived from filaggrin.
  • citrullinated peptides (4 peptides derived from the ⁇ chain and 1 derived from the ⁇ chain of fibrin), which are each individually recognized. by at least 40% of the sera analyzed, and therefore appear to carry major epitopes.
  • these peptides two are recognized by the majority of the sera, and furthermore have complementary reactivity profiles encompassing all the sera analyzed. Each of these sera recognizes indeed one and / or the other of these peptides. This suggests that these two peptides carry structural motifs representative of a very large majority of the different motifs recognized by the ACPAs.
  • the peptides according to the invention have a size of at least 5 amino acids, preferably a size of 5 to 25 amino acids, and most preferably a size of 10 to 20 amino acids.
  • Citrullinated peptides according to the invention may for example be obtained from fragments of fibrin or fibrinogen natural, recombinant, or synthesis, by the action of peptidyl arginine deiminase (PAD); they can also be obtained by peptide synthesis, by directly incorporating one or more citrulline residues, into the synthesized peptide.
  • PAD peptidyl arginine deiminase
  • Citrullinated peptides according to the invention also include derivatives of the peptides SEQ ID NO: 1 to 4, and 12 or fragments thereof, defined above, said derivatives bearing modifications intended to improve their recognition by the AAPCs: by way of examples of such derivatives, mention may be made of: cyclized peptides; retro-type peptides, in which L-amino acids are linked in a reverse sequence to that of the peptide to be reproduced; peptides of retro-inverso type , consisting of amino acids of the D series (instead of the amino acids of the L series of natural peptides) chained in a reverse sequence to that of the peptide to be reproduced.
  • peptides in which the terminal carboxyl (COOH) function is replaced by a carboxamide function (CONH 2 ).
  • particularly preferred peptides are those in which the C-terminal residue is a citrullyl residue whose carboxyl function is replaced by a carboxamide function.
  • the present invention also relates to any peptide recognized by AAPC present in the serum of patients with rheumatoid arthritis, and containing at its C-terminus a citrullyl residue whose carboxyl function is replaced by a carboxamide function.
  • said peptide contains in its sequence at least one other citrullyl residue.
  • said peptide comprises from 5 to 25 amino acids.
  • the replacement of the carboxyl function of the C-terminal citrulline residue by a carboxamide function can make it possible to increase the reactivity of the peptide with the AAPCs, or, where appropriate, to make reagents with AAPCs, peptides which are not naturally reactive. .
  • Citrullinated peptides in accordance with the invention also include derivatives of the peptides SEQ ID NO: 1 to 4, and 12 or fragments thereof, as defined above, said derivatives carrying modifications intended to facilitate their synthesis and / or improve their stability.
  • derivatives include peptides including amino acids whose carboxyl groups are esterified or converted to amide groups and / or amino acids an amino group is alkylated, for example methylated or acetylated.
  • the amine and carboxyl groups of the peptides may be present in the form of the salt corresponding to the base or the acid.
  • mimotope peptides can be obtained by screening libraries of citrullinated peptides whose sequences are defined from those of the peptides SEQ ID No. 1, 2, 3, 4, 12 of the present invention, used in this context as “model peptides. ".
  • these peptide libraries are made by synthesis of different peptides of size between 10 and 20, preferably between 12 and 17 amino acids, in particular 15 amino acids.
  • Each of these peptides retains at least 2, preferably at least 4, advantageously at least 6, particularly preferably at least 8, and most advantageously at least 10 amino acids, including at least one citrullyl residue, of the model peptide sequence. chosen at the same positions as on said model peptide, the other positions being variable.
  • citrullinated mimotope peptides can be used alone or in combination with other citrullinated peptides and preferably in combination with at least one of the other peptides of the invention, in a diagnostic test of RA to recognize the ACPAs.
  • the subject of the present invention is also the use of the peptides according to the invention, as defined above, for detecting the presence of AAPC in a biological sample, as part of the in vitro diagnosis of RA.
  • compositions which can be used to detect the presence of AAPC in a biological sample as part of the in vitro diagnosis of RA, which compositions are characterized in that they comprise at least one peptide which conforms to the invention.
  • compositions in accordance with the invention may associate various peptides selected from among the peptides according to the invention, or may associate one or more peptides in accordance with the invention with one or more citrullinated peptides derived in particular from filaggrin.
  • an antigenic composition according to the invention, it comprises at least one peptide of sequence SEQ ID NO: 1, and at least one peptide of sequence SEQ ID NO: 2, as defined above. .
  • This composition has a very broad spectrum of reactivity, and can also allow to detect the PR at an early stage.
  • composition according to the invention may further comprise a peptide of sequence SEQ ID NO: 3 and / or a peptide of sequence SEQ ID NO: 4 and / or a peptide of sequence SEQ ID NO: 12, as defined above.
  • compositions in accordance with the invention may, where appropriate, be in the form of multi-peptide compositions, in which the constituent peptides are associated with each other or with a carrier molecule generally by covalent bonding.
  • MAP antigenic multi-peptides
  • TAM Proc Natl Acad Sci USA, 85, 5409-13, 1988
  • This detection method may be implemented by means of a kit comprising at least one peptide or an antigenic composition according to the invention, and, where appropriate, buffers and reagents suitable for the constitution of a reaction medium allowing the formation of an antigen / antibody complex, and / or means for detecting said antigen / antibody complex.
  • said kit comprises a peptide or an antigenic composition according to the invention, immobilized on a solid support.
  • suitable solid carriers include microtiter plates, cones of VIDAS ® device (marketed by bioMérieux), beads, microbeads or microparticles, strips, etc ....
  • Said kit may also comprise reference samples, such as one or more negative serum (s) and one or more positive serum (s).
  • EXAMPLE 1 Demonstration of the heterogeneity of the reaction of the CSAPs with cisagulin-derived citrate peptides and the production of mixtures of serotypes representing the various reactive profiles.
  • mixtures hereinafter referred to as mixtures: "A” and “B” were each constituted by mixing in equal parts 10 sera representing different profiles of reactivity on peptides "filaggrin”.
  • Table II Serum Profile Mixed 97.0459 1 AT 97.0388 3 97.1436 4 97.0169 6 97.0530 7 97.0311 8 97.0506 9 97.0468 10 97.0796 11 97.0907 12 97.1715 1 B 97.0524 1 97.0323 2 97.0794 4 95.0256 5 97.1795 5 97.1474 9 97.0244 10 97.1548 11 97.1210 12
  • mixtures A and B are therefore representative of the heterogeneity of specificity of the AAPC + sera.
  • the peptides tested were obtained from the ⁇ chain sequence and the fibrin ⁇ chain sequence [portion respectively corresponding to residues 36-635 and 45-491 of the A ( ⁇ ) chains (reference NP Accession: NP_068657) and B ( ⁇ ) (reference SWISSPROT FIBB_HUMAN Prim. Accession: P02675) of fibrinogen].
  • the sequences of residues 1 to 635 and 1 to 491 of the A ( ⁇ ) and B ( ⁇ ) chains of fibrinogen are also respectively represented in the attached sequence listing under the numbers SEQ ID NO: 10 and SEQ ID NO: 11, and on the Figure 1 A and B.
  • the sequences indicated in bold on the Figure 1 are those of the signal sequences of the proteins followed by those of their fibrinopeptides (A and B, respectively).
  • Each ⁇ or ⁇ chain of fibrin was segmented into contiguous sequences of 15 amino acids, and all the peptides comprising at least one arginyl residue were chosen.
  • a second set of 15 amino acid peptides overlapping the first, so as to refocus the terminal arginyl residue in the sequence, was chosen.
  • a peptide corresponding to residues 621-629 of the ⁇ chain of fibrin was synthesized. A total of 72 peptides including 41 derivatives of the ⁇ chain of fibrin and 31 derivatives of its ⁇ chain were chosen.
  • the arginyl residue form (native form) and the form in which all arginyl residues were substituted with citrullyl residues (citrullinated form) were synthesized according to the Merrifield solid phase method with purity. ⁇ 60% [NeoMPS Company (Strasbourg, France)].
  • the nomenclature used is the following: the origin name of the polypeptide chain ( ⁇ or ⁇ ) of the fibrinogen from which the sequence is derived, then position in this sequence of the amino-terminal residue of the peptide-position of the carboxy-terminal residue of the peptide. These positions are numbered relative to the N-terminus of fibrinogen. Cit indicates that it is a citrullinated form of the peptide. The position of the arginyl residue which is substituted by a citrullyl residue is indicated as an index. Only the citrullinated forms of the peptides are presented.
  • peptides were tested after irradiation of irradiated polystyrene plates (Nunc Maxisorp) in three different buffers (acetate pH 5.0, PBS pH 7.4 and carbonate pH 9.0), in order to optimize the chances of passive fixation.
  • peptides (10 ⁇ g / ml) which had very heterogeneous isoelectric points (ranging from 4 to 12 for non-citrullinated forms).
  • the specific reactivity of the mixtures of sera with respect to the citrullinated peptides corresponded to the difference between the obtained OD with the conjugated peptide and that obtained with the corresponding native peptide (delta OD).
  • the results correspond to the average of 2 determinations. Any citrullinated peptide which makes it possible to obtain a delta OD greater than 0.250 for at least one of the two mixtures A and B after coating in at least one of the three buffers, was considered to be reactive.
  • EXAMPLE 3 REACTIVITY PROFILE OF CITRULLINED PEPTIDES REACTING WITH ACPA.
  • the 14 peptides carrying the most reactive epitopes were tested independently with the 20 sera constituting mixtures A and B, in order to evaluate the reactivity profile of each of these peptides.
  • the tests were carried out in ELISA under the same conditions as in Example 2 above, except that, for each pair of peptides, the coating buffer chosen was used to obtain the highest reactivity. against this peptide during the screening (the buffer where the sum of the delta OD respectively obtained for the A and B mixtures of sera was maximum).
  • the dilutions of the sera were adjusted so that they had equivalent avidity for the entire descriminated fibrinogen.
  • the dilution was chosen which makes it possible to obtain an OD of 1 in ELISA on the descriminated fibrinogen (Nogueira L, 2002, cited above). Dilutions ranged from 1/20 to 1/2700.
  • ELISA plates were coated with the peptide ⁇ 60-74Cit 60,72,74 whose C-terminal function of the carboxy-terminal citrullyl residue is not amidated (form carrying a terminal COOH function, hereinafter referred to as "non-amidated form”). ") with the ⁇ 60-74Cit 60,72,74 peptide whose C-terminal function of the carboxy-terminal residue citrullyl is amidated (form carrying a terminal function CONH 2, hereinafter designated” amidated form ”) and non-peptide citrullinated ⁇ 60-74 (whose C-terminal function of the carboxy-terminal arginyl residue is not amidated), all diluted in PBS.
  • Example 2 The mixtures A and B of sera described in Example 1 were tested according to the method described in Example 2.
  • the specific reactivity of the peptide in non-amidated or amidated form corresponded to difference between the OD obtained with these two citrullinated peptides and that obtained with the non-citrullinated peptide ⁇ 60-74.
  • the reactivity of the amidated form of the peptide appeared to be significantly higher than that of the non-amidated form, which was, however, significant.
  • the results correspond to the average of two experiments, each comprising two determinations.
  • Table VI Table VI peptide Mix of serums Delta DO ⁇ 60-74Cit 60.72,74 unmediated Mixture A 0.30 Mix B 1.16 ⁇ 60-74Cit 60.72,74 amide Mixture A 2.13 Mix B 2.74

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biophysics (AREA)
  • Medicinal Chemistry (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • Toxicology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Hematology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Claims (10)

  1. Isoliertes Peptid, das von Autoantikörpern gegen citrullinierte Proteine (AAPC) erkannt wird, die sich im Serum von Patienten befinden, die an rheumatoider Polyarthritis (PR) leiden, dadurch gekennzeichnet, dass es wenigstens einen Citrullylrest umfasst, und dadurch, dass es ausgewählt ist aus der Gruppe bestehend aus:
    a) einem durch die Sequenz X1 PAPPPISGGGYX2AX3 (SEQ ID NO:1) definierten Peptid, in dem X1, X2 und X3 jeweils einen Citrullylrest oder einen Arginylrest darstellen und wenigstens einer der Reste X2 oder X3 ein Citrullylrest ist;
    b) einem durch die Sequenz GPX1VVEX2HQSACKDS (SEQ ID NO:2) definierten Peptid, in dem X1 und X2 jeweils einen Citrullylrest oder einen Arginylrest darstellen und wenigstens einer der Reste X1 oder X2 ein Citrullylrest ist;
    c) einem durch die Sequenz SGIGTLDGFX1HX2HPD (SEQ ID NO:3) definierten Peptid, in dem X1 und X2 jeweils einen Citrullylrest oder einen Arginylrest darstellen und wenigstens einer der Reste X1 oder X2 ein Citrullylrest ist;
    d) einem durch die Sequenz VDIDIKIX1SCX2GSCS (SEQ ID NO:4) definierten Peptid, in dem X1 und X2 jeweils einen Citrullylrest oder einen Arginylrest darstellen und wenigstens einer der Reste X1 oder X2 ein Citrullylrest ist;
    e) einem durch die Sequenz X1GHAKSX2PVX3GIHTS (SEQ ID NO:12) definierten Peptid, in dem X1, X2 und X3 jeweils einen Citrullylrest oder einen Arginylrest darstellen und wenigstens einer der Reste X1, X2 oder X3 ein Citrullylrest ist;
    f) einem Peptid, das wenigstens 5 aufeinanderfolgende Aminosäuren, darunter wenigstens einen Citrullylrest, von einem der obigen Peptide a) bis e) umfasst.
  2. Peptid nach Anspruch 1, dadurch gekennzeichnet, dass es ausgewählt ist aus der Gruppe bestehend aus:
    - einem durch die Sequenz SEQ ID NO:1 definierten Peptid, in dem wenigstens X3 ein Citrullylrest ist, oder einem Peptid, das ein Fragment mit wenigstens 5 aufeinanderfolgenden Aminosäuren dieser Sequenz umfasst, die diesen Citrullylrest enthalten;
    - einem durch die Sequenz SEQ ID NO:2 definierten Peptid, in dem wenigstens X2 ein Citrullylrest ist, oder einem Peptid, das ein Fragment mit wenigstens 5 aufeinanderfolgenden Aminosäuren dieser Sequenz umfasst, die diesen Citrullylrest enthalten;
    - einem durch die Sequenz SEQ ID NO:3 definierten Peptid, in dem wenigstens X2 ein Citrullylrest ist, oder einem Peptid, das ein Fragment mit wenigstens 5 aufeinanderfolgenden Aminosäuren dieser Sequenz umfasst, die diesen Citrullylrest enthalten;
    - einem durch die Sequenz SEQ ID NO:4 definierten Peptid, in dem wenigstens X1 ein Citrullylrest ist, oder einem Peptid, das ein Fragment mit wenigstens 5 aufeinanderfolgenden Aminosäuren dieser Sequenz umfasst, die diesen Citrullylrest enthalten;
    - einem durch die Sequenz SEQ ID NO:12 definierten Peptid, in dem wenigstens X3 ein Citrullylrest ist, oder einem Peptid, das ein Fragment mit wenigstens 5 aufeinanderfolgenden Aminosäuren dieser Sequenz umfasst, die diesen Citrullylrest enthalten.
  3. Peptid nach Anspruch 2, dadurch gekennzeichnet, dass es ausgewählt ist aus der Gruppe bestehend aus:
    - einem durch die Sequenz SEQ ID NO:1 definierten Peptid, in dem X1, X2 und X3 Citrullylreste sind, oder einem Peptid mit wenigstens 16 Aminosäuren, das diese Sequenz umfasst;
    - einem durch die Sequenz SEQ ID NO:2 definierten Peptid, in dem X1 und X2 Citrullylreste sind, oder einem Peptid, das ein Fragment mit wenigstens 5 aufeinanderfolgenden Aminosäuren dieser Sequenz umfasst, die diese Citrullylreste enthalten;
    - einem durch die Sequenz SEQ ID NO:3 definierten Peptid, in dem X1 und X2 Citrullylreste sind, oder einem Peptid, das ein Fragment mit wenigstens 5 aufeinanderfolgenden Aminosäuren dieser Sequenz umfasst, die diese Citrullylreste enthalten;
    - einem durch die Sequenz SEQ ID NO:4 definierten Peptid, in dem X1 und X2 Citrullylreste sind, oder einem Peptid, das ein Fragment mit wenigstens 5 aufeinanderfolgenden Aminosäuren dieser Sequenz umfasst, die diese Citrullylreste enthalten;
    - einem durch die Sequenz SEQ ID NO:12 definierten Peptid, in dem X1, X2 und X3 Citrullylreste sind, oder einem Peptid, das ein Fragment mit wenigstens 10 aufeinanderfolgenden Aminosäuren dieser Sequenz umfasst, die diese Citrullylreste enthalten.
  4. Peptid nach einem der Ansprüche 1 bis 3, in dem die terminale Carboxylfunktion (COOH) durch eine Carboxamidfunktion (CONH2) ersetzt ist.
  5. Verwendung eines Peptids nach einem der Ansprüche 1 bis 4 zum Nachweis der Anwesenheit von für PR spezifischen AAPC in einer biologischen Probe.
  6. Antigene Zusammensetzung, dadurch gekennzeichnet, dass sie wenigstens ein Peptid nach einem der Ansprüche 1 bis 4 umfasst.
  7. Antigene Zusammensetzung nach Anspruch 6, dadurch gekennzeichnet, dass sie ein Peptid der Sequenz SEQ ID NO:1 und ein Peptid der Sequenz SEQ ID NO:2 nach einem der Ansprüche 1 bis 4 umfasst.
  8. Antigene Zusammensetzung nach einem der Ansprüche 6 oder 7, dadurch gekennzeichnet, dass sie ein Peptid der Sequenz SEQ ID NO:3 und/oder ein Peptid der Sequenz SEQ ID NO:4 und/oder ein Peptid der Sequenz SEQ ID NO:12 nach einem der Ansprüche 1 bis 4 umfasst.
  9. Verfahren zum Nachweis der Anwesenheit von AAPC in einer biologischen Probe, wobei das Verfahren dadurch gekennzeichnet ist, dass es umfasst:
    - Inkontaktbringen der biologischen Probe mit wenigstens einem Peptid nach einem der Ansprüche 1 bis 4 oder einer antigenen Zusammensetzung nach einem der Ansprüche 6 bis 8 unter Bedingungen, die die Bildung eines Antigen/Antikörper-Komplexes mit den gegebenenfalls in der Probe befindlichen AAPC erlauben;
    - Nachweis, mit allen geeigneten Mitteln, des gegebenenfalls gebildeten Antigen/Antikörper-Komplexes.
  10. Verfahren zum Nachweis der Anwesenheit von AAPC in einer biologischen Probe, wobei das Verfahren dadurch gekennzeichnet ist, dass es umfasst:
    - Bereitstellen eines ersten citrullinierten Peptids, das mit einem Peptid, wie es in einem der Ansprüche 1 bis 4 definiert ist, um die Bindung an diese AAPC konkurrieren kann;
    - Inkontaktbringen des ersten Peptids mit der biologischen Probe unter Bedingungen, die die Bildung eines Antigen/Antikörper-Komplexes mit den gegebenenfalls in der Probe befindlichen AAPC erlauben;
    - Nachweis, mit allen geeigneten Mitteln, des gegebenenfalls gebildeten Antigen/Antikörper-Komplexes.
EP05815291A 2004-11-04 2005-11-03 Von fibrin abgeleitete citrullinpeptide, die durch für rheumatoide arthritis spezifische autoantikörper erkannt werden, und deren verwendung Active EP1814901B1 (de)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
FR0411782A FR2877345B1 (fr) 2004-11-04 2004-11-04 Peptides citrullines derives de la fibrine reconnus par des auto-anticorps specifiques de la polyarthrite rhumatoide, et leurs utilisations
FR0413711A FR2879604B1 (fr) 2004-12-22 2004-12-22 Peptides citrullines derives de la fibrine reconnus par des auto-anticorps specifiques de la polyarthrite rhumatoide, et leurs utilisations
FR0508422 2005-08-08
PCT/FR2005/002736 WO2006048556A1 (fr) 2004-11-04 2005-11-03 Peptides citrullines derives de la fibrine reconnus par des auto-anticorps specifiques de la polyartrhite rhumatoide, et leurs utilisations

Publications (2)

Publication Number Publication Date
EP1814901A1 EP1814901A1 (de) 2007-08-08
EP1814901B1 true EP1814901B1 (de) 2008-07-16

Family

ID=35677372

Family Applications (1)

Application Number Title Priority Date Filing Date
EP05815291A Active EP1814901B1 (de) 2004-11-04 2005-11-03 Von fibrin abgeleitete citrullinpeptide, die durch für rheumatoide arthritis spezifische autoantikörper erkannt werden, und deren verwendung

Country Status (7)

Country Link
US (2) US8207299B2 (de)
EP (1) EP1814901B1 (de)
JP (1) JP5060300B2 (de)
AT (1) ATE401338T1 (de)
DE (1) DE602005008277D1 (de)
ES (1) ES2310853T3 (de)
WO (1) WO2006048556A1 (de)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8683158B2 (en) 2005-12-30 2014-03-25 Intel Corporation Steering system management code region accesses
FR2900657B1 (fr) * 2006-05-03 2009-04-17 Univ Toulouse Identification de modulateurs de l'activation des macrophages, utilisables pour le traitement de la polyarthrite rhumatoide
US20100047256A1 (en) * 2007-01-25 2010-02-25 Imperial Innovations Limited Methods
ES2307421B1 (es) * 2007-04-30 2009-09-28 Consejo Superiorde Investigaciones Cientificas (Csic) Polipeptido quimerico fibrina-filagrina citruinado capaz de detectar los anticuerpos generados en la artritis reumatoide.
JP5611831B2 (ja) * 2007-12-03 2014-10-22 エスキューアイ・ダイアグノスティクス・システムズ・インコーポレイテッドＳＱＩ Ｄｉａｇｎｏｓｔｉｃｓ Ｓｙｓｔｅｍｓ Ｉｎｃ． リウマチ性関節炎自己抗体との免疫反応性合成ペプチド
FR2908134B1 (fr) * 2007-12-04 2012-10-12 Univ Toulouse 3 Paul Sabatier Identification de modulateurs de l'activation des macrophages, utilisables pour le traitement de la polyarthrite rhumatoide
EP2325195A1 (de) 2009-11-23 2011-05-25 Toscana Biomarkers S.r.l. Virale citrullinierte Peptide und Verwendungen dafür
EP2402368A1 (de) 2010-07-02 2012-01-04 Toscana Biomarkers S.r.l. Histoncitrullinierte Peptide und deren Verwendungen
EP2527841A1 (de) 2011-05-25 2012-11-28 Toscana Biomarkers S.r.l. Verfahren zur Diagnose rheumatoider Arthritis
US10424553B2 (en) * 2016-10-31 2019-09-24 Micron Technology, Inc. Semiconductor devices with underfill control features, and associated systems and methods
FR3108515B1 (fr) * 2020-03-26 2022-03-25 Ct Hospitalier Universitaire Toulouse Colonne d’aphérèse pour le traitement de la polyarthrite rhumatoïde
GB202103164D0 (en) * 2021-03-08 2021-04-21 Adiga Life Sciences Inc Therapy

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2795735B1 (fr) 1999-07-01 2001-09-07 Univ Toulouse Derives citrullines de la fibrine et leur utilisation pour le diagnostic ou le traitement de la polyarthrite rhumatoide
NL1019540C2 (nl) 2001-12-11 2003-07-01 Stichting Tech Wetenschapp Werkwijze voor het detecteren van auto-antilichamen van patienten die lijden aan reumatoïde artritis, peptide en assaykit.

Also Published As

Publication number Publication date
ATE401338T1 (de) 2008-08-15
JP5060300B2 (ja) 2012-10-31
JP2008518898A (ja) 2008-06-05
US8207299B2 (en) 2012-06-26
US9249208B2 (en) 2016-02-02
EP1814901A1 (de) 2007-08-08
WO2006048556A1 (fr) 2006-05-11
US20090028885A1 (en) 2009-01-29
ES2310853T3 (es) 2009-01-16
US20130028922A1 (en) 2013-01-31
DE602005008277D1 (de) 2008-08-28

Similar Documents

Publication Publication Date Title
EP1814901B1 (de) Von fibrin abgeleitete citrullinpeptide, die durch für rheumatoide arthritis spezifische autoantikörper erkannt werden, und deren verwendung
EP0929669B1 (de) Von filaggrin abgeleitete antigene und deren anwendung in der diagnose von rheumatischer polyarthritis
CN1192153A (zh) aPL免疫反应性肽和其缀合物以及治疗aPL抗体-介导的疾病的方法
JP2000512981A (ja) ａＰＬ免疫応答性ペプチド、その結合体およびａＰＬ抗体媒介病理のための処置方法
EP1619205A1 (de) Citrullin-enthaltende Fibrin-derivate und ihre Verwendung zur Diagnose und Behandlung von Rheumatischer Arthritis
Gainer Precursors of vasopressin and oxytocin
FR2482861A1 (fr) Procede de preparation d'un antigene et d'un anticorps du glucagon intestinal
EP1204865B1 (de) Synthetische verbindungen mit zwei epitopen für immunoassays
EP0569309B2 (de) Synthetische Polypeptide vom Hepatitis C-Virus, verwendbar für den Nachweis des Virus
JPH08233811A (ja) Ｉ型コラーゲン検出用の抗原及び抗体
EP1042366A1 (de) Peptidische epitope, von gegen filaggrin gerichteten, im serum der an rheumatoiden polyarthritis leidenden patienten anwesenden autoantikörpern anerkannt
EP2026830B1 (de) Die makrophagenaktivität modluierende peptide zur behandlung von rheumatoider arthritis
EP0491014B1 (de) Peptide von sm-d-antigen, deren benützung zum nachweis von disseminierten lupus-erythemateux
FR2879604A1 (fr) Peptides citrullines derives de la fibrine reconnus par des auto-anticorps specifiques de la polyarthrite rhumatoide, et leurs utilisations
EP0724016A1 (de) Toxoplasma gondii mimotype Polypeptide und Anwendungen davon
FR2877345A1 (fr) Peptides citrullines derives de la fibrine reconnus par des auto-anticorps specifiques de la polyarthrite rhumatoide, et leurs utilisations
Rinas et al. Characterization of recombinant factor XIIIa produced in Saccharomyces cerevisiae
FR2737209A1 (fr) Peptide capable d'etre reconnu par des anticorps reconnaissant l'antigene c33 du virus de l'hepatite c
FR2680174A1 (fr) Nouveaux composes peptidiques, inhibiteurs de l'adsorption du virus hiv sur ses cellules cibles.
WO2021045182A1 (ja) トリプターゼ活性測定用基質
CN1225015A (zh) aPL免疫反应性肽、其缀合物以及aPL抗体介导的疾病的治疗方法
FR2761993A1 (fr) Peptides synthetiques utilisables dans les essais biologiques pour la detection des infections dues aux virus vih 1 groupe 0

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20070530

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

RIN1 Information on inventor provided before grant (corrected)

Inventor name: SEBBAG, MIREILLE

Inventor name: SERRE, GUY,RESIDENCE DU LAC-APPARTEMENT 46

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

DAX Request for extension of the european patent (deleted)
GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

Free format text: NOT ENGLISH

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REF Corresponds to:

Ref document number: 602005008277

Country of ref document: DE

Date of ref document: 20080828

Kind code of ref document: P

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

Free format text: LANGUAGE OF EP DOCUMENT: FRENCH

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2310853

Country of ref document: ES

Kind code of ref document: T3

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081116

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080716

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080716

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080716

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081016

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081216

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080716

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080716

REG Reference to a national code

Ref country code: IE

Ref legal event code: FD4D

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080716

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080716

Ref country code: IE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080716

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080716

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080716

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080716

BERE Be: lapsed

Owner name: BIOMERIEUX

Effective date: 20081130

26N No opposition filed

Effective date: 20090417

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20081130

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20081130

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080716

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080716

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20090117

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20081103

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080716

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20091130

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20091130

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20081017

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 11

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 12

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 13

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20231120

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20231123

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 20231120

Year of fee payment: 19

Ref country code: IT

Payment date: 20231124

Year of fee payment: 19

Ref country code: FR

Payment date: 20231013

Year of fee payment: 19

Ref country code: DE

Payment date: 20231121

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20240124

Year of fee payment: 19